EP2277867B1 - Composés, compositions pharmaceutiques les contenants et leur utilisation pour traiter le cancer - Google Patents

Composés, compositions pharmaceutiques les contenants et leur utilisation pour traiter le cancer Download PDF

Info

Publication number
EP2277867B1
EP2277867B1 EP10183590A EP10183590A EP2277867B1 EP 2277867 B1 EP2277867 B1 EP 2277867B1 EP 10183590 A EP10183590 A EP 10183590A EP 10183590 A EP10183590 A EP 10183590A EP 2277867 B1 EP2277867 B1 EP 2277867B1
Authority
EP
European Patent Office
Prior art keywords
methyloxy
quinazolin
methyl
oxy
amine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP10183590A
Other languages
German (de)
English (en)
Other versions
EP2277867A2 (fr
EP2277867A3 (fr
Inventor
Kenneth D. Rice
Csabe J. Peto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Symphony Evolution Inc
Original Assignee
Symphony Evolution Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Symphony Evolution Inc filed Critical Symphony Evolution Inc
Publication of EP2277867A2 publication Critical patent/EP2277867A2/fr
Publication of EP2277867A3 publication Critical patent/EP2277867A3/fr
Application granted granted Critical
Publication of EP2277867B1 publication Critical patent/EP2277867B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • This invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention relates to quinazolines which inhibit, regulate and/or modulate kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions.
  • Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i.e., virtually all aspects of cell life in one-way or another depend on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
  • Protein kinases can be categorized as receptor type or non-receptor type.
  • Receptor-type tyrosine kinases have an extracellular, a transmembrane, and an intracellular domain, while non-receptor type tyrosine kinases are wholly intracellular.
  • Receptor-type tyrosine kinases are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about twenty different subfamilies of receptor-type tyrosine kinases have been identified.
  • Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.
  • the insulin subfamily includes INS-R, IGF-IR, and IR-R.
  • the PDGF subfamily includes the PDGF-alpha and beta-receptors, CSFIR, c-kit and FLK-II.
  • the FLK family which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flit-1).
  • KDR kinase insert domain receptor
  • FLK-1 fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • flit-1 flit-like tyrosine kinase-1
  • the non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors.
  • the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk.
  • the Src subfamily of enzymes has been linked to oncogenesis.
  • kinase modulation relates to oncological indications.
  • modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatinib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, NJ) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers (GIST).
  • Gleevec is a c-Kit and Abl kinase inhibitor.
  • Anti-angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. As well, cell antiproliferative agents are desirable to slow or stop the growth of tumors.
  • Hennequin L. F. et al (1999, J. Med. Chem. 42, 5369-5389 ) disclose 4-anilinoquinazoline derivatives which are receptor tyrosine kinase inhibitors and have been developed as potential agents for the treatment of angioproliverative diseases such as cancer.
  • VEGF receptors are previously described targets for small molecule inhibition.
  • Eph receptors comprise the largest family of receptor tyrosine kinases and are divided into two groups, EphA and EphB, based on their sequence homology.
  • the ligands for the Eph receptors are ephrin, which are membrane anchored. Ephrin A ligands bind preferentially to EphA receptors whilst ephrin B ligands bind to EphB receptors. Binding of ephrin to Eph receptors causes receptor autophosphorylation and typically requires a cell-cell interaction since both receptor and ligand are membrane bound.
  • Eph receptor tyrosine kinases and their ephrin ligands play important roles in a variety of processes during embryonic development and also in pathological angiogenesis and potentially metastasis. Therefore modulation of Eph receptor kinase activity should provide means to treat or prevent disease states associated with abnormal cell proliferation such as those described above.
  • the epidermal growth factor receptor (EGFR, HER1, erbB1) is part of a family of plasmam membrane receptor tyrosine kinases that control cellular growth, proliferation and apoptosis.
  • the ligand for EGFR is the epidermal growth factor and dysregulation of the EGFR signal transduction pathway has been implicated in tumorigenesis and cancer progression thus making it a clinically relevant target for novel anticancer treatments Drevs J et al 2003 Curr Drug Targets 4, 113-121 ; Ciardiello F and Tortora G. 2001 Clin. Cancer Res. 7, 2958-2970 ; Thomas M. 2002 Semin Onc. Nurs. 18, 20-27 ).
  • EGFR is overexpressed in different human cancers especially non-small cell lung cancer and glioblastomas. In these cancers, EGFR overexpression is commonly associated with advanced disease and poor prognosis ( Baselga J et al 1999 Semin. Oncol. 26, 78-83 ).
  • the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of tyrosine kinases, particularly ephrin and EGFR receptor kinases, is desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and is an object of this invention.
  • the present invention discloses compounds for modulating kinase activity, particularly ephrin receptor kinase (from herein denoted "ephrin”) activity and/or EGFR activity; also disclosed are methods of treating diseases mediated by such activity utilizing the compounds and pharmaceutical compositions thereof.
  • Diseases mediated by ephrin include diseases characterized in part by abnormal cell migration and invasion and angiogenesis associated with tumor growth.
  • Diseases mediated by EGF driven signal transduction include, diseases characterized by abnormal levels of cell proliferation (i.e. tumor growth) and programmed cell death (apoptosis).
  • Diseases mediated by both ephrin and EGF include diseases characterized by both abnormal cell proliferation and angiogenesis which are associated with tumor growth.
  • Inhibitors that are selective for a particular kinase are disclosed in this invention.
  • compounds that inhibit, regulate and/or modulate the signal transduction receptor tyrosine kinase families, family members, or otherwise related sets of kinases are disclosed in this invention.
  • Such related kinase families may include receptor-type tyrosine kinases of the HER, FLK and insulin subfamilies, which demonstrate similarity in both structure and broad biochemical function.
  • quinazolines disclosed herein include "spectrum selective" kinase modulators.
  • Specific kinase modulators are defined as quinazolines disclosed herein that inhibit, regulate and/or modulate signal transduction across various subfamilies of receptor-type tyrosine kinases including those of ephrin and EGFR receptor tyrosine kinase subfamilies.
  • the invention discloses methods of screening for modulators of receptor tyrosine kinase activity, for example activity of ephrin and EGFR.
  • the methods comprise combining a composition of the invention, a receptor tyrosine kinase, and at least one candidate agent and determining the effect of the candidate agent on the kinase activity.
  • kits comprising one or more containers filled with one or more of the ingredients of pharmaceutical compounds and/or compositions of the present invention, including, one or more tyrosine receptor kinase activity modulators as described herein.
  • kits can also include, for example, other compounds and/or compositions (for example, diluents, permeation enhancers, lubricants, and the like), a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.
  • the invention also discloses a diagnostic agent comprising a compound of the invention and, optionally, pharmaceutically acceptable adjuvants and excipients.
  • the present invention provides compounds which can modulate receptor kinase activity, particularly ephrin and EGFR, pharmaceutical compositions thereof and such compounds for use in treating cancer.
  • the compounds according to present invention are selected from N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3aR,5r,6aS)-2-methyloctahydrocyclopenta [c]pyrrol-5-yl]methyl)oxy)-6-(methyloxy)quinazolin-4-amine and N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine.
  • compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities.
  • Disease states which can be treated by the methods and compositions provided herein include cancer (further discussed below), immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy.
  • cancer cancer
  • immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis
  • cardiovascular diseases such as artheroscrosis, myocardioinfarction, ischemia, stroke and restenosis
  • other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy.
  • the cells may not be in a hyper- or hypo-proliferative and/or migratory state (abnormal state) and still require treatment.
  • the cells may be proliferating "normally", but proliferation and migration enhancement may be desired.
  • reduction in "normal” cell proliferation and/or migration rate may be desired.
  • the present invention discloses a compound for modulating tyrosine kinase activity of Formula I, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein,
  • the compound is according to paragraph [0024], wherein M 3 is -CH 2 -.
  • the compound is according to paragraph [0025], wherein Z is -NR 5 -.
  • the compound is according to paragraph [0026], wherein R 1 is CH 3 -.
  • the compound is according to paragraph [0027], wherein of I is selected from: wherein R 2a is selected from -H, F, Cl, and Br; and R 2b and R 2c are each independently selected from F, Cl, and Br.
  • the compound is according to paragraph [0028], wherein M 2 is a monocyclic five- to seven-membered heterocyclyl or a five- to six-membered heteroaryl, each optionally substituted with between one and three of R 50 .
  • the compound is according to paragraph [0029], wherein M 2 is selected from the group consisting of morpholinyl, thiazolyl, oxadiazolyl, tetrahydropyranyl, and oxazepanyl, each optionally substituted with between one and three of R 50 .
  • M 1 is selected from the group consisting of -H, dimethylaminomethyl, (4-methylpiperizin-1-yl)methyl, piperidinyl, 1-methylpiperidin-4-yl, morpholin-4-ylmethyl, and phenylmethyl.
  • the compound is according to paragraph [0028], wherein M 1 is either a three- to seven-membered saturated carbocyclyl or a heterocyclyl with one or two annular heteroatoms, wherein the either of the aforementioned are optionally substituted with at least one of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, R 10 (R 11 )N-, and hydroxy, provided there are no geminal heteroatom substitutions; and wherein R 10 and R 11 are each independently C 1 -C 3 alkyl.
  • the compound is according to paragraph [0024], wherein M 1 -M 2 -M 3 -M 4 - together are according to formula II ; wherein X 1 , X 2 , and optionally X 3 , represent the atoms of a saturated bridged ring system, said saturated bridged ring system containing up to three annular heteroatoms represented by any of X 1 , X 2 , and X 3 ; wherein,
  • the compound is according to paragraph [0035], wherein Z is -NR 5 -.
  • the compound is according to paragraph [0036], wherein R 2 is selected from -H, halogen, trihalomethyl, -CN, -NO 2 , -OR 3 , and optionally substituted lower alkyl.
  • the compound is according to paragraph [0037], wherein R 1 is an unsubstituted C 1-3 alkyl.
  • the compound is according to paragraph [0038], wherein the saturated bridged ring system has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].
  • the compound is according to paragraph [0039], wherein Y is selected from -CH 2 CH 2 -, -CH 2 -, and absent.
  • the compound is according to paragraph [0041], wherein R 5 is -H.
  • the compound is according to paragraph [0042], wherein R 1 is methyl.
  • the compound is according to paragraph [0043], wherein the saturated bridged ring system has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0].
  • the compound is according to paragraph [0044], wherein said saturated bridged ring system contains one or two annular nitrogens, said one or two annular nitrogens are selected from -NR 8 -, when X 1 , and a bridgehead nitrogen, when X 2 .
  • the compound is according to paragraph [0045], wherein E is absent.
  • the compound is according to paragraph [0046], wherein said saturated bridged ring system is according to formula III ; wherein A is selected from -O-, -S(O) 0-2 -, -NR 8 -, and absent; and e is 0 or 1.
  • the compound is according to paragraph [0048], wherein A is selected from -NR 8 -, wherein R 8 is selected from -H, optionally substituted lower alkyl, -CO 2 R 3 , -C(O)N(R 3 )R 4 , -SO 2 R 4 , and -C(O)R 3 ; -O-; and absent.
  • the compound is according to paragraph [0049], wherein of I is selected from: wherein R 2a , R 2b , and R 2c are each independently selected from F, Cl, and Br.
  • the compound is according to paragraph [0050], wherein R 2a is F, R 2b is Cl, and R 2c is either Cl or Br.
  • the compounds of are according to paragraph [0052], wherein Y is either -CH 2 - or absent.
  • the compounds of are according to paragraph [0053], wherein one of R 11 and R 12 is -OR 13 , wherein R 13 is selected from -H, -C(O)R 4 , and optionally substituted lower alkyl; and R 10 and the other of R 11 and R 12 are both -H.
  • the compounds of are according to paragraph [0053], wherein one of R 11 and R 12 is -F; and R 10 and the other of R 11 and R 12 are both -H.
  • the compound is according to paragraph [0053], wherein q is two or three.
  • each R 2 is independently selected from -F, -Cl, -Br, -CF 3 , -CH 3 , and -OR 25 ; wherein R 25 is either methyl or aryl, each optionally substituted with one to three halogens.
  • the compound is according to paragraph [0045], wherein said saturated bridged ring system is according to either formula V or formula VI ; wherein R 8 is selected from -H, optionally substituted lower alkyl, -CO 2 R 3 , -C(O)N(R 3 )R 4 , -SO 2 R 4 , and -C(O)R 3 .
  • the compound is according to paragraph [0059], wherein Y is either -CH 2 - or absent.
  • the compound is according to paragraph [0060], wherein of I is selected from: wherein R 2a , R 2b , and R 2c are each independently selected from F, Cl, and Br.
  • the compound is according to paragraph [0061], wherein R 2a is F, R 2b is Cl, and R 2c is either Cl or Br.
  • the compound is according to paragraph [0062], wherein R 8 is methyl or ethyl.
  • the compound is according to paragraph [0046], wherein said saturated bridged ring system is according to formula VII ; wherein A is selected from -O-, -S(O) 0-2 -, -NR 8 -, -CR 6 R 7 -, and absent.
  • the compound is according to paragraph [0064], wherein R 3 is selected from -H and optionally substituted alkyl.
  • the compound is according to paragraph [0065], wherein A is either -C(R 6 )R 7 - or absent.
  • the compound is according to paragraph [0066], wherein A is either -CH 2 - or absent.
  • the compound is according to paragraph [0069], wherein of I is selected from: wherein R 2a , R 2b , and R 2c are each independently selected from F, Cl, and Br.
  • the compound is according to paragraph [0070], wherein R 2a is F, R 2b is Cl, and R 2c is either Cl or Br.
  • the compound is according to paragraph [0043], wherein the saturated bridged ring system has a geometry selected from the group consisting of [3.3.1], [3.2.1], and [2.2.1].
  • the compound is according to paragraph [0072], wherein said saturated bridged ring system contains one or two annular nitrogens, said one or two annular nitrogens are selected from -NR 8 -, when X 1 , and a bridgehead nitrogen, when X 2 .
  • the compound is according to paragraph [0073], wherein said saturated bridged ring system is according to formula VIII or formula IX ; wherein R 8 is selected from -H, optionally substituted lower alkyl, -CO 2 R 3 , -C(O)N(R 3 )R 4 , -SO 2 R 4 , and -C(O)R 3 ; and R 26 is C 1-3 alkyl.
  • the compound is according to paragraph [0074], wherein Y is -CH 2 CH 2 -; and E is either absent or -N(R 9 )-.
  • the compound is according to paragraph [0076], wherein of I is selected from: R 2b , and R 2c are each independently selected from F, Cl, and Br.
  • the compound is according to paragraph [0077], wherein R 2a is F, R 2b is Cl, and R 2c is either Cl or Br.
  • the compound is according to paragraph [0078], wherein R 8 is methyl or ethyl.
  • the compound is according to paragraph [0024], selected from Table 1; compounds according to the invention are indicated with an asterisk: Table 1 Entry Name Structure 1 N-(3,4-dichloro-2-fluorophenyl)-7-( ⁇ [(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine 2 N-(4-bromo-3-chloro-2-fluorophenyl)-7-( ⁇ [(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine 3 7-( ⁇ 1(3aR,5r,6aS)-2-acetyloctahydrocyclopenta[c]pyrrol-5-yl]methyl
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the claims and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a compound according to the claims for use in the inhibition of EGFR or ErbB2.
  • Another aspect of the invention is a compound according to the claims for use in a method of treating cancer.
  • a substituent "R” may reside on any atom of the fused ring system, assuming replacement of a depicted (for example the -NH- in the formula above), implied (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, "X" equals -CH-) from one of the ring atoms, so long as a stable structure is formed.
  • the "R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • the two "R's" may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof, inclusively.
  • C 8 alkyl may refer to an n-octyl, iso -octyl, cyclohexylethyl, and the like.
  • Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s -butyl, t -butyl, isobutyl, pentyl, hexyl and the like.
  • Higher alkyl refers to alkyl groups containing more that eight carbon atoms.
  • alkyl groups are those of C 20 or below.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from three to thirteen carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like.
  • alkyl residue having a specific number of carbons all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either “butyl” or “C 4 alkyl” is meant to include n -butyl, sec -butyl, isobutyl, t -butyl, isobutenyl and but-2-yne radicals; and "propyl” or “C 3 alkyl” each include n -propyl, propenyl, and isopropyl.
  • Alkylene refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to ten carbon atoms, for example, methylene, ethylene, propylene, n -butylene and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, fully saturated. Examples of alkylene include ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), dimethylpropylene (-CH 2 C(CH 3 ) 2 CH 2 -), and cyclohexylpropylene (-CH 2 CH 2 CH(C 6 H 13 )).
  • Alkylidene refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to ten carbon atoms, for example, ethylidene, propylidene, n -butylidene, and the like. Alkylidene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, double bond unsaturation. The unsaturation present includes at least one double bond and a double bond can exist between the first carbon of the chain and a carbon atom of the rest of the molecule to which it is attached.
  • Alkylidyne refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms having from two to ten carbon atoms, for example, propylid-2-ynyl, n -butylid-1-ynyl, and the like. Alkylidyne is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment and, specifically, triple bond unsaturation. The unsaturation present includes at least one triple bond and a triple bond can exist between the first carbon of the chain and a carbon atom of the rest of the molecule to which it is attached.
  • alkylene when optionally substituted, may contain alkyl substitution which itself contains unsaturation.
  • 2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains an n -butylid-3-ynyl radical with a vinyl substituent at the 2-position of said radical.
  • Alkoxy refers to the group -O-alkyl, for example including from one to eight carbon atoms of a straight, branched, cyclic configuration, unsaturated chains, and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
  • Substituted alkoxy refers to the group -O-(substituted alkyl), the substitution on the alkyl group generally containing more than only carbon (as defined by alkoxy).
  • One exemplary substituted alkoxy group is "polyalkoxy” or -O-optionally substituted alkylene-optionally substituted alkoxy, and includes groups such as -OCH 2 CH 2 OCH 3 , and glycol ethers such as polyethyleneglycol and -O(CH 2 CH 2 O) x CH 3 , where x is an integer of between about two and about twenty, in another example, between about two and about ten, and in a further example between about two and about five.
  • Another exemplary substituted alkoxy group is hydroxyalkoxy or -OCH 2 (CH 2 ) y OH, where y is for example an integer of between about one and about ten, in another example y is an integer of between about one and about four.
  • Acyl refers to groups of from one to ten carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.
  • ⁇ -Amino Acids refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available ⁇ -amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline.
  • a "side chain of an ⁇ -amino acid” refers to the radical found on the ⁇ -carbon of an ⁇ -amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like.
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -N(H)R or -N(R)R where each R is independently selected from the group: optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.
  • Aryl refers to aromatic six- to fourteen-membered carbocyclic rings include, for example, benzene, naphthalene, indane, tetralin, fluorene and the like.
  • Arylalkyl refers to a residue in which an aryl moiety is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. The aryl, alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted. "Lower arylalkyl” refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons.
  • Exo-alkenyl refers to a double bond that emanates from an annular carbon, and is not within the ring system, for example the double bond depicted in the formula below.
  • fused-polycyclic or “fused ring system” refers to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms. Typically, a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with a plurality of halogens, but not necessarily a plurality of the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
  • Heteroatom refers to O, S, N, or P.
  • Heterocyclyl refers to a stable three- to fifteen-membered ring radical that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems, and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quatemized; and the ring radical may be partially or fully saturated or aromatic.
  • heterocyclyl radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepin
  • Heteroalicyclic refers specifically to a non-aromatic heterocyclyl system radical.
  • Heteroaryl refers specifically to an aromatic heterocyclyl system radical.
  • Heterocyclylalkyl refers to a residue in which a heterocyclyl is attached to a parent structure via one of an alkylene, alkylidene, or alkylidyne radical. Examples include (4-methylpiperazin-1-yl) methyl, (morpholin-4-yl) methyl, 2-(oxazolin-2-yl) ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like.
  • the heterocyclyl, alkylene, alkylidene, or alkylidyne radical portion of an arylalkyl group may be optionally substituted.
  • “Lower heterocyclylalkyl” refers to an arylalkyl where the "alkyl" portion of the group has one to six carbons.
  • Hydrocarbyl refers to a hydrocarbon residue, generally.
  • hydrocarbyl can be modified to mean more specific structures, for example "a saturated or mono- or poly-unsaturated C 3 -C 14 mono- or fused-polycyclic hydrocarbyl optionally containing one, two, or three annular heteroatoms per ring” means a mono- or polycyclic (for example a bridged bicyclic) ring system, having between three and fourteen-ring atoms, that contains only carbon ring atoms, but optionally can contain up to three heteratoms per ring and/or unsaturation.
  • Optionally substituted refers to all subsequent modifiers in a term, for example in the term “optionally substituted arylC 1-8 alkyl,” optional substitution may occur on both the “C 1-8 alkyl” portion and the “aryl” portion of the molecule; and for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum.
  • optional substitution include, but are not limited to alkyl, halogen, alkoxy, hydroxy, oxo, carbamyl, acylamino, sulfonamido, carboxy, alkoxycarbonyl, acyl, alkylthio, alkylsulfonyl, nitro, cyano, amino, alkylamino, cycloalkyl and the like.
  • “Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo[2.2.1]heptane and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system.”
  • Spirocyclyl or “spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of the aforementioned saturated bridged ring system can be a shared atom between the saturated bridged ring system (rings B and B') and a spirocyclyl (ring A) attached thereto, as depicted below.
  • a spirocyclyl can be either carbocyclic or heterocyclic
  • Substituted alkyl, aryl, and heterocyclyl refer respectively to alkyl, aryl, and heterocyclyl, wherein one or more (for example up to about five, in another example, up to about three) hydrogen atoms are replaced by a substituent independently selected from the group: optionally substituted alkyl (for example, fluoroalkyl), optionally substituted alkoxy, alkylenedioxy (for example methylenedioxy), optionally substituted amino (for example, alkylamino and dialkylamino), optionally substituted amidino, optionally substituted aryl (for example, phenyl), optionally substituted arylalkyl (for example, benzyl), optionally substituted aryloxy (for example, phenoxy), optionally substituted arylalkyloxy (for example, benzyloxy), carboxy (-COOH), carboalkoxy (i.e., acyloxy or -OOCR), carboxyalkyl (i.
  • “Sulfanyl” refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), and -S-(optionally substituted heterocyclyl).
  • “Sulfinyl” refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-optionally substituted aryl), and -S(O)-(optionally substituted heterocyclyl).
  • “Sulfonyl” refers to the groups: -S(O 2 )-H, -S(O 2 )-(optionally substituted alkyl), -S(O 2 )-optionally substituted aryl), -S(O 2 )-(optionally substituted heterocyclyl), -S(O 2 )-(optionally substituted alkoxy), -S(O 2 )-optionally substituted aryloxy), and -S(O 2 )-(optionally substituted heterocyclyloxy).
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e. saturated ring structures) can contain two substitution groups.
  • Some of the compounds disclosed herein may have imino, amino, oxo or hydroxy substituents off aromatic heterocyclyl systems.
  • imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
  • ACD/Name available from Advanced Chemistry Development, Inc. of Toronto, Canada. This software derives names from chemical structures according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).
  • IUPAC International Union of Pure and Applied Chemistry
  • IUBMB International Union of Biochemistry and Molecular Biology
  • CAS Chemical Abstracts Service
  • the compounds disclosed herein, or their pharmaceutically acceptable salts may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.
  • the compounds disclosed herein and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds may also exist as geometric isomers.
  • Stable constructs for the saturated bridged ring system as represented by X 1 , X 2 , and optionally X 3 of formula II include but are not limited to motifs such as: 1) where heteroatoms of a ring or bridge thereon are bonded directly to each other, for example a bridge containing a sulfonamide, 2) where heteroatoms of a ring or bridge thereon are separated by only one carbon, for example a urea, carbamate, acetal, aminal, thioacetal, thioaminal, amidine, guanidine, and the like, 3) where heteroatoms of a ring or bridge thereon are separated by two or more carbons, for example an -NHCH 2 CH 2 O- bridge, and the like, and 4) where heteroatoms in the bridged ring system are separated by more than two carbon atoms, for example wherein the bridged ring system is a decahydro-isoquinoline.
  • optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the R- and S-isomers may be resolved by methods known to those skilled in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomers enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human.
  • Kinase-dependent diseases or conditions refer to pathologic conditions that depend on the activity of one or more protein kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).
  • ocular diseases diabetic retinopathy, age-related macular degeneration, and the like
  • inflammation psoriasis, rheumatoid arthritis, and the like.
  • phosphatases can also play a role in "kinase-dependent diseases or conditions" as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth.
  • abnormal levels of cell proliferation i.e. tumor growth
  • apoptosis programmed cell death
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.
  • the therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • “Cancer” refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (
  • “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, trifluoro
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
  • salts of primary, secondary, and tertiary amines substituted amines including naturally occurring substituted amines, cyclic amines
  • organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
  • Treating covers the treatment of a disease-state in a human, which disease-state is characterized by abnormal cellular proliferation, and invasion and includes at least one of: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i.e., arresting its development; and (iii) relieving the disease-state, i.e., causing regression of the disease-state.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
  • Compositions of the invention may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
  • the protein is bound to a support, and a compound of the invention is added to the assay.
  • the compound of the invention is bound to the support and the protein is added.
  • Classes of candidate agents among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells.
  • assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.) and the like.
  • the determination of the binding of the candidate agent to, for example ephrin or EGFR protein may be done in a number of ways.
  • the candidate agent (the compound of the invention) is labeled, for example, with a fluorescent or radioactive moiety and binding determined directly.
  • a labeled agent for example a compound of the invention in which at least one atom has been replaced by a detectable isotope
  • washing off excess reagent for example a compound of the invention in which at least one atom has been replaced by a detectable isotope
  • Various blocking and washing steps may be utilized as is known in the art.
  • label herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, for example, radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc.
  • Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc.
  • the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above.
  • the label can directly or indirectly provide a detectable signal.
  • ephrin or EGFR protein may be labeled at tyrosine positions using 125 I, or with fluorophores.
  • more than one component may be labeled with different labels; using 125 I for the proteins, for example, and a fluorophor for the candidate agents.
  • the compounds of the invention may also be used as competitors to screen for additional drug candidates.
  • "Candidate bioactive agent” or “drug candidate” or grammatical equivalents as used herein describe any molecule, for example, protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for bioactivity. They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. In the case where protein binding or activity is screened, some embodiments exclude molecules already known to bind to that particular protein.
  • exogenous agents include candidate agents, which do not bind the target protein in its endogenous native state, termed herein as "exogenous" agents.
  • exogenous agents further exclude antibodies to ephrin or EGFR.
  • Candidate agents can encompass numerous chemical classes, though typically they are organic molecules having a molecular weight of more than about 100 and less than about 2,500 daltons.
  • Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl, hydroxyl, ether, or carboxyl group, for example at least two of the functional chemical groups.
  • the candidate agents often comprise cyclical carbon or heterocyclyl structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.
  • Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof.
  • Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification to produce structural analogs.
  • the binding of the candidate agent is determined through the use of competitive binding assays.
  • the competitor is a binding moiety known to bind to ephrin or EGFR, such as an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be competitive binding as between the candidate agent and the binding moiety, with the binding moiety displacing the candidate agent.
  • the candidate agent is labeled. Either the candidate agent, or the competitor, or both, is added first to ephrin or EGFR for a time sufficient to allow binding, if present. Incubations may be performed at any temperature that facilitates optimal activity, typically between 4°C and 40°C.
  • Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component is then added, and the presence or absence of the labeled component is followed, to indicate binding.
  • the competitor is added first, followed by the candidate agent.
  • Displacement of the competitor is an indication the candidate agent is binding to ephrin or EGFR and thus is capable of binding to, and potentially modulating, the activity of ephrin or EGFR.
  • either component can be labeled.
  • the presence of label in the wash solution indicates displacement by the agent.
  • the candidate agent is labeled, the presence of the label on the support indicates displacement.
  • the candidate agent is added first, with incubation and washing, followed by the competitor.
  • the absence of binding by the competitor may indicate the candidate agent is bound to ephrin or EGFR with a higher affinity.
  • the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to ephrin or EGFR.
  • ephrin or EGFR may be of value to identify the binding site of, for example, ephrin or EGFR. This can be done in a variety of ways. In one embodiment, once ephrin or EGFR has been identified as binding to the candidate agent, ephrin or EGFR is fragmented or modified and the assays repeated to identify the necessary components for binding.
  • Modulation is tested by screening for candidate agents capable of modulating the activity of ephrin or EGFR comprising the steps of combining a candidate agent with ephrin or EGFR, as above, and determining an alteration in the biological activity of ephrin or EGFR.
  • the candidate agent should both bind to (although this may not be necessary), and alter its biological or biochemical activity as defined herein.
  • the methods include both in vitro screening methods and in vivo screening of cells for alterations in cell viability, morphology, and the like.
  • differential screening may be used to identify drug candidates that bind to native ephrin or EGFR, but cannot bind to modified ephrin or EGFR.
  • Positive controls and negative controls may be used in the assays. For example, all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of samples is for a time sufficient for the binding of the agent to the protein. Following incubation, samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples may be counted in a scintillation counter to determine the amount of bound compound.
  • reagents may be included in the screening assays. These include reagents like salts, neutral proteins, for example, albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components may be added in any order that provides for the requisite binding.
  • Scheme 1 depicts a general synthetic route for compounds of the invention and is not intended to be limiting. Specific examples are described subsequently to this general synthetic description.
  • a benzoic ester 1 where R is typically but not necessarily a methyl radical and P is typically but not necessarily an alkyl group, is O-alkylated at the oxygen para to the carboxylate group with an electrophile to afford a substituted derivative 2.
  • P is typically a lower alkyl group, but can be a protecting group that is removed later in a synthesis. When P is a lower alkyl group it can possess functionality initially, or be derivitized to contain such functionality at various stages of the synthesis.
  • the group, E 1 represents either a protecting group, for example benzyl, or a group that either has moieties present in compounds of the invention or possesses functionality that serve as a precursors to such groups.
  • Aromatic ring nitration and reduction of the corresponding nitro group are carried out in a regio- and chemoselective manner by methods well known in the art to give anthranilate derivative 3.
  • Formation of quinazolin-4-one 4 is carried out by methods well known in the art, for example by heating 3 in formamide solution in the presence of ammonium formate, or for another example by heating directly with formamidine hydrochloride.
  • Introduction of 4-position functionality is carried out by methods known in the art.
  • quinazolin-4-one 4 is converted to an intermediate quinazoline 5, where "L” represents a leaving group, for example chlorine.
  • Quinazoline 5 is then converted to 6 by reaction with a range of nucleophiles, for example amines, alcohols, and thiols.
  • group "Z" is either left “as is” or converted at some subsequent stage to a derivative thereof.
  • Z is -NH-
  • the hydrogen on the nitrogen may optionally be replaced with an alkyl group, or when Z is sulfur, then that sulfur atom may be oxidized to, for example, a sulfone.
  • Compound 6 may represent a compound of the invention or, for example when E 1 serves as a protecting group, E 1 may be removed to provide phenol 7.
  • Introduction of a group E 2 is carried out by methods well established in the art, for example alkylation with an appropriately derivatized alkyl halide.
  • 1,4:3,6-dianhydro-2- O- methyl-5- O- (methylsulfonyl)-D-glucitol To a solution of 1,4:3,6-dianhydro-2- O- methyl-D-glucitol (1.19g, 7.4 mmol) in dichloromethane was added pyridine (1mL, 12.36 mmol) followed by methanesulfonyl chloride (0.69mL, 8.92 mmol) and the mixture was allowed to stir at room temperature over 12 hours. The solvent was removed and the amorphous residue was partitioned between ethyl acetate and aqueous hydrochloric acid (for example 0.1M HCl).
  • reaction mixture was poured into water (100mL), and extracted with ethyl acetate (3 x 50mL). The organic layers were washed with 5% LiCl (2 x 50mL), and brine (50mL) then dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica (97:3 dichloromethane/methanol) gave a solid, which was dissolved in methanol (50mL), and treated with 4M HCl in 1,4-dioxane (5mL).
  • 1,4:3,6-dianhydro-5- O -(phenylcarbonyl)-D-fructose ethylene glycol acetal A solution of 1,4:3,6-dianhydro-5- O -(phenylcarbonyl)-D-fructose (2.00g, 8.06 mmol), ethylene glycol (5.00g, 80.6 mmol), and p -toluenesulfonic acid (1.53g, 8.06 mmol) in benzene (100mL) was refluxed for 90 min using a Dean-Stark Trap apparatus.
  • reaction mixture was diluted with ethyl acetate (100mL), washed with saturated aqueous sodium bicarbonate (2 x 50mL) then brine (50mL), and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography on silica (1:1 hexane/ethyl acetate) provided 1.44g (61% yield) of 1,4:3,6-dianhydro-5- O -(phenylcarbonyl)-D-fructose ethylene glycol acetal as a colorless solid.
  • 1,4:3,6-dianhydro-D-fructose ethylene glycol acetal To a solution of 1,4:3,6-dianhydro-5- O -(phenylcarbonyl)-D-fructose ethylene glycol acetal (1.44g, 4.93 mmol) in methanol (40mL) was added 50% aqueous sodium hydroxide (0.38 g, 4.75 mmol) and the mixture was stirred at room temperature for 30 minutes.
  • 1,4:3,6-dianhydro-5- O -(methylsulfonyl)-D-fructose ethylene glycol acetal To a solution of 1,4:3,6-dianhydro-D-fructose ethylene glycol acetal (0.74g, 3.93 mmol) and triethylamine (1.20g, 11.86 mmol) in dichloromethane (40mL) was added methanesulfonyl chloride (0.90g, 7.88 mmol) at 0°C under nitrogen. The solution was warmed to room temperature and stirred for 13 h.
  • reaction mixture was poured into water (50mL), and extracted with ethyl acetate (3 x 30mL). The organic layers were washed with 5% LiCl (2 x 25mL), and brine (25mL) then dried over anhydrous sodium sulfate and concentrated.
  • 1,4:3,6-dianhydro-2-deoxy-2-methylidene-D- arabino -hexitol To a solution of 1,4:3,6-dianhydro-2-deoxy-2-methylidene-5- O -(phenylcarbonyl)-D-arabino-hexitol (329mg, 1.34 mmol) in methanol (10mL) was added 50% aqueous sodium hydroxide (95mg, 1.19 mmol) and the mixture was stirred at room temperature for 30 minutes.
  • 1,4:3,6-dianhydro-2-deoxy-2-methylidene-5- O -(methylsulfonyl)-D- arabino- hexitol To a solution of 1,4:3,6-dianhydro-2-deoxy-2-methylidene-D- arabino -hexitol (135mg, 0.95 mmol) and triethylamine (288mg, 2.85 mmol) in dichloromethane (10mL) was added methanesulfonyl chloride (222mg, 1.94 mmol) at 0°C under nitrogen. The solution was warmed to room temperature and stirred for 18 h.
  • Methyl 3,6-anhydro-5- O -(phenylcarbonyl)- ⁇ -L-glucofuranoside To a solution of 1,4:3,6-dianhydro-2-deoxy-5- O -(phenylcarbonyl)-L-arabino-hex-1-enitol (1.00g, 4.3 mmol) in methanol (17 mL) at -4°C was added 3-chloroperoxybenzoic acid (85%, 1.35g, 8.6 mmol), and the resulting mixture was slowly warmed to room temperature and stirred for 18 hours.
  • Methyl 3,6-anhydro-2- O -methyl-5- O -(phenylcarbonyl)- ⁇ -Irglucofuranoside A mixture of methyl 3,6-anhydro-5- O -(phenylcarbonyl)- ⁇ -L-glucofuranoside (1.03g, 3.7 mmol), silver (I) oxide (0.85g, 3.7 mmol) and methyl iodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60°C for 1 hour.
  • Methyl 3,6-anhydro-2- O -methyl- ⁇ -D-idofuranoside A solution of methyl 3,6-anhydro-2- O -methyl-5- O -(phenylcarbonyl)- ⁇ -L-glucofuranoside (820mg, 3.1mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (10mL) was stirred at room temperature for 30 minutes.
  • Methyl 3,6-anhydro-2- O -methyl-5- O -(methylsulfonyl)- ⁇ -L-glucofuranoside Methyl 3,6-anhydro-2- O -methyl- ⁇ -D-idofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at 0°C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at 0°C for 1 hour then at room temperature for 2 hours.
  • 3,6-anhydro-2- O -methyl-5- O -(phenylcarbonyl)- ⁇ -L-glucofuranoside 3,6-Anhydro-5- O -(phenylcarbonyl)- ⁇ -L-glucofuranose (576 mg, 2.2 mmol) was added to a mixture of sodium hydride (60% oil dispersion, 346 mg, 8.7 mmol) and methyl iodide (0.54mL, 8.7 mmol) in 5 mL of DMF at 0°C and the resulting mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and quenched with water (5 mL).
  • Methyl 3,6-anhydro-2- O -methyl-5- O -(methylsulfonyl)- ⁇ -L-glucofuranoside A solution of methyl 3,6-anhydro-2- O -methyl-5- O -(phenylcarbonyl)- ⁇ -L-glucofuranoside (230mg, 0.92 mmol) and 50% sodium hydroxide (74 mg, 0.92 mmol) in methanol (5 mL) was stirred at room temperature for 30 minutes.
  • the mixture was adsorbed on silica gel (2g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to afford a colorless oil which was employed directly in the next step, 140 mg, 0.72 mmol, 95% yield.
  • the alcohol was dissolved in dichloromethane (5 mL) and pyridine (121 ⁇ L, 1.03 mmol) was added at 0°C. Methanesulfonyl chloride (27 ⁇ L, 0.88 mmol) was added and the resulting mixture was stirred at 0°C for 1 hour then at room temperature for 2 hours.
  • reaction mixture was cooled then adsorbed on silica gel (10g) and purified by flash chromatography (silica gel, 5-35% ethyl acetate in hexanes) to give 3,6-anhydro-1,2- O -(1-methylethylidene)-5- O -(phenylcarbonyl)- ⁇ -L-glucofuranose as colorless oil, 0.85g, 74% yield.
  • 3,6-Anhydro-1,2- O -(1-methylethylidene)-5- O -(methylsulfonyl)- ⁇ -L-glucofuranose A solution of 3,6-anhydro-1,2- O -(1-methylethylidene)-5- O- (phenylcarbonyl)- ⁇ -L-glucofuranose (850mg) and 50% sodium hydroxide (111 mg) in methanol (10mL) was stirred at room temperature for 30 minutes.
  • the mixture was then adsorbed on silica gel (5g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) and the alcohol intermediate, 390 mg, 70% yield, was used immediately in the next step.
  • the alcohol was dissolved in dichloromethane (10 mL) and pyridine (0.32 mL) at 0°C. Methanesulfonyl chloride (0.12 mL) was added and the resulting mixture was stirred at 0°C for 1 hour then at room temperature for 2 hours.
  • (3 S ,8a S )-Hexahydro-1 H -pyrrolo[2,1- c ][1,4]oxazin-3-ylmethyl acetate (3 S ,8a S )-3-(Chloromethyl)hexahydro-1 H -pyrrolo[2,1- c ][1,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylformamide (25 mL) at 140°C for 20 h. The mixture was partitioned between ethyl acetate and water.
  • (3 S ,8a S )-Hexahydro-1 H -pyrrolo[2,1- c ][1,4]oxazin-3-ylmethanol (3 S ,8a S )-Hexahydro-1 H -pyrrolo[2,1- c ][1,4]oxazin-3-ylmethyl acetate (2.36 g, 11.9 mmol) was treated with sodium methoxide (25 wt% solution in methanol; 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and a solution of 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) was added slowly.
  • (3S,8aS)-hexahydro-1 H -pyrrolo[2,1- c ][1,4]oxazin-3-ylmethyl methanesulfonate (3 S ,8a S )-Hexahydro-1 H -pyrrolo[2,1- c ][1,4]oxazin-3-ylmethanol (1.00 g, 6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (2.4 mL, 17.3 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.93 mL, 12.0 mmol).
  • Octahydro-2 H -quinolizin-3-ylmethyl methanesulfonate Octahydro-2 H -quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0°C followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate.
  • (3 S ,8a S )-3-( ⁇ [(1,1-Dimethylethyl)(dimethyl)silyl]oxy ⁇ methyl)hexahydropyrrolo [1,2- a ]pyrazin-1(2 H )-one To a solution of (3 S ,8a S )-3-(hydroxymethyl) hexahydropyrrolo[1,2- a ]pyrazin-l(2 H )-one (1.49 g, 8.82 mmol) in dimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmol).
  • 1,2-Dideoxy-1-[(2 S )-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy) carbonyl]amino]-D- glycero -hexitol To a solution of 2-deoxy-2- ⁇ [(phenylmethyloxy) carbonyl]amino ⁇ -D-glycero-hexopyranose (5.0 g, 0.016 mol) in methanol (500 mL) was added L-proline methyl ester hydrochloride (2.8 g, 0.022 mol) and sodium cyanoborohydride (3.4 g, 0.054 mol). The solution was heated to 64 °C for 14 h.
  • Methyl 1-[(2 S )-3-hydroxy-2-( ⁇ [(phenylmethyl)oxy]carbonyl ⁇ amino)propyl]-L-prolinate 1,2-dideoxy-1-[(2 S )-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy) carbonyl]amino]-D- glycero -hexitol (6.81 g, 0.016 mol) was taken into water (100 mL) and the resulting solution was cooled to 0°C. Sodium periodiate (14.8 g, 0.069 mol) dissolved in water was added dropwise and the resulting mixture was stirred at 0°C for 2 h.
  • the reaction mixture was partitioned with dichloromethane (3x100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in methanol (200 mL) and the resulting solution was cooled to 0°C. Sodium borohydride (1.98 g, 0.052 mol) was added and the reaction mixture was stirred for 1 h at 0°C. The reaction mixture was concentrated in vacuo and partitioned with dichloromethane and saturated aqueous ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.
  • Methyl 1-[(2 S )-3-[(methylsulfonyl)oxy]-2-( ⁇ [(phenylmethyl)oxy]carbonyl ⁇ amino) propyl]-L-prolinate Methyl 1-[(2 S )-3-hydroxy-2-( ⁇ [(phenylmethyl)oxy]carbonyl ⁇ amino) propyl]-L-prolinate (200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of 4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) and triethylamine (0.125 mL, 0.891 mmol) and the resulting mixture was cooled to 0 °C.
  • 1,1-Dimethylethyl (3a R ,6a S )-5-(hydroxymethyl)hexahydrocyclopenta[ c ]pyrrole-2(1 H )-carboxylate Under a nitrogen atmosphere, borane tetrahydrofuran complex (1M in THF, 42 mL, 41.9 mmol) was diluted with tetrahydrofuran (42 mL) and cooled with an ice bath. Neat 2,3-dimethylbut-2-ene (5.0 mL, 41.9 mmol) was added in portions over 0.25 h and the solution was stirred at 0°C for 3 h.
  • the crude reaction mixture was diluted with 100 mL of 10% methanol in ethyl acetate and washed with water (5 x 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • the crude reaction mixture was diluted with 100 mL 10% methanol in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1x 30 mL), water (1 x 30 mL) and brine (1 x 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • the solution was heated to 95°C for 12 h.
  • the reaction mixture was concentrated in vacuo.
  • the residue was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2x 30 mL) and brine.
  • the organic layer was dried over anhydrous sodium sulfate, filtered then concentrated and purified by HPLC (reverse-phase, water/acetonitrile/0.1% TFA). Upon removal of solvent the product was taken up in 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2x 30 mL) and brine.
  • the solution was warmed to room temperature and stirred for 1.5 h.
  • the solvents were removed and the residue was partitioned between water and 10% methanol in ethyl acetate.
  • the layers were separated and the aqueous layer was extracted with 10% methanol in ethyl acetate (3 x 50 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.
  • 1,1-Dimethylethyl (3a R ,6a S )-5-(hydroxy)-hexahydrocyclopenta[ c ]pyrrole-2(1 H )-carboxylate Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of 1,1-dimethylethyl (3a R ,6a S ) -5-oxo-hexahydrocyclopenta[ c ] pyrrole-2(1 H )-carboxylate (0.45 g, 2.00 mmol) in 10 mL methanol at 0°C and the reaction mixture was stirred for 1 h at this temperature.
  • 1,1-Dimethylethyl (3a R ,6a S )-5- ⁇ [(methylsulfonyl)oxy] ⁇ hexahydrocyclopenta[ c ]pyrrole-2(1 H )-carboxylate Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to a solution of 1,1-dimethylethyl (3a R ,6a S )-5-(hydroxy)-hexahydrocyclopenta[ c ]pyrrole-2(1 H )-carboxylate (0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 mL dichloromethane at 0°C and the reaction mixture was stirred for 1 h at room temperature.
  • the crude reaction mixture was diluted with 100 mL 10% methanol in ethyl acetate and washed with saturated aqueous sodium bicarbonate (1x 30 mL), water (1 x 30 mL) and brine (1 x 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • the solution was heated to 95°C for 12 h.
  • the reaction mixture was concentrated in vacuo.
  • the residue was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2x 30 mL) and brine.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2x 30 mL) and brine.
  • Hexahydro-1 H -[1,4]oxazino[3,4- c ][1,4]oxazin-3-ylmethyl acetate A suspension of (3 R ,9a S )-3-(chloromethyl)hexahydro-1 H -[1,4]oxazino[3,4- c ][1,4]oxazine (1.97 g, 10.3 mmol) and potassium acetate (10.1 g, 102 mmol) in DMF (20.0 mL) was stirred at 140°C for 16 h, and then at 150°C for another 12 h.
  • the reaction mixture was concentrated in vacuo and the residue was partitioned between 10% methanol in ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted (3 x 50 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • the crude residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in methanol and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8.
  • N -(3,4-Dichlorophenyl)-7-[(2- ⁇ [(3- endo )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl] amino ⁇ ethyl)oxy]-6-(methyloxy)quinazolin-4-amine To a DMF solution (3.0 mL) of 7-[(2-aminoethyl)oxy]- N -(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine hydrochloride (56.8 mg, 0.137 mmol) at room temperature, was added glacial acetic acid (3 drops), (1 R ,5 S )-8-methyl-8-azabicyclo[3.2.1]octan-3-one (49.0 mg, 0.137 mmol), and sodium triacetoxyborohydride (43.0 mg, 0.205 mmol).
  • N -(3,4-Dichlorophenyl)-7- ⁇ [(3- exo )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy ⁇ -6-(methyloxy)quinazolin-4-amine hydrochloride A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (0.150 g, 0.322 mmol), (3- endo )-3-[(methylsulfonyl)methyl]-8-azabicyclo[3.2.1]octane (0.106 g, 0.483 mmol), and potassium carbonate (0.220 g, 1.60 mmol) in N,N-dimethylacetamide (1.1 mL) was heated in a sealed tube at 100°C for 12 h, followed by 48 h at room temperature.
  • the crude reaction mixture was filtered through celite using methanol eluent, and the solvents were removed in vacuo.
  • the residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent, the product was taken up in methanol and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, then taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (0.050 mL).
  • Solvent was removed in vacuo and the residue partitioned with 10% methanol in ethyl acetate and water.
  • the aqueous layer was made basic with saturated aqueous sodium bicarbonate.
  • the layers were separated and the aqueous layer was further extracted with 10% methanol in ethyl acetate (2x).
  • the combined organic extracts were dried over anhydrous sodium sulfate, filtered and the concentrated in vacuo.
  • the resulting mixture was heated to 200°C for 0.5 h then poured carefully onto wet ice, which was allowed to melt.
  • the aqueous solution was carefully made basic using solid sodium bicarbonate and the resulting mixture was filtered using water and 10% methanol in ethyl acetate as eluent. The layers were separated and the aqueous layer was extracted with 10% methanol in ethyl acetate.
  • N -(3,4-Dichlorophenyl)-6-(methyloxy)-7- ⁇ [(8a R )-tetrahydro-1 H -[1,3]thiazolo[4,3- c ][1,4]oxazin-6-ylmethyl]oxy ⁇ quinazolin-4-amine trifluoroacetate A solution of (8a R )-6-(chloromethyl)tetrahydro-1 H -[1,3]thiazolo[4,3- c ][1,4]oxazine (11.6 mg, 0.0599 mmol), 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (30.0 mg, 0.0644 mmol), and potassium carbonate (45.0 mg, 0.326 mmol) in N,N-dimethylacetamide (1.0 mL) was heated in a sealed tube to 150°C for 12 h.
  • 1,1-Dimethylethyl (3- endo )-3- ⁇ 2-[(methylsulfonyl)oxy]ethyl ⁇ -8-azabicyclo[3.2.1] octane-8-carboxylate To a solution of 1,1-dimethylethyl (3- endo )-3-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (30.3 mg, 1.19 mmol) in dichloromethane (4.0 mL), was added triethylamine (0.5 mL, 3.56 mmol) and the solution was cooled to 0°C under nitrogen.
  • Methanesulfonyl chloride (0.11 mL, 1.42 mmol) was added slowly and mixture was allowed to warm to room temperature and stirred for 1h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 35.1 mg (89%) of 1,1-dimethylethyl (3- endo )-3- ⁇ 2-[(methylsulfonyl)oxy]ethyl ⁇ -8-azabicyclo[3.2.1]octane-8-carboxylate, which was carried forward without purification.
  • 1,1-Dimethylethyl (3- endo )-3-(2- ⁇ [4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy ⁇ ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate To a solution of 1,1-dimethylethyl (3- endo )-3- ⁇ 2-[(methylsulfonyl)oxy]ethyl ⁇ -8-azabicyclo[3.2.1]octane-8-carboxylate (0.175 g, 0.526 mmol) in N,N-dimethylacetamide (3.5 mL) was added 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (0.490 g, 1.05 mmol) and potassium carbonate (0.728 g, 5.26 mmol), and the reaction
  • N-(3,4-Dichlorophenyl)-7-( ⁇ 2-[(3- endo )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]ethyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride To a solution of 7-( ⁇ 2-[(3- endo )-8-azabicyclo[3.2.1]oct-3-yl]ethyl ⁇ oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy) quinazolin-4-amine hydrochloride (0.346 g, 0.678 mmol) in formic acid (2.7 mL), was added aqueous formaldehyde (37%, 0.27 mL, 4.07 mmol) and the mixture was heated to 110°C for 5h, then allowed to cool to room temperature.
  • the solution was concentrated in vacuo and the residue was taken up in methanol and treated with AG 1-X8 resin (hydroxide form) to pH 8.
  • the mixture was filtered and concentrated then the residue purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA) and the pure fractions lyophillized.
  • the residue was taken up in methanol and neutralized with AG 1-X8 resin (hydroxide form) to pH 8 then filtered and concentrated.
  • the residue was taken into methanol (3 mL) and treated with 4.0 M hydrogen chloride in dioxane to pH 2.
  • 1,4:3,6-dianhydro-2- O -[4-(methyloxy)carbonyl-2-(methyloxy)phenyl]-5- O- (methylsulfonyl)-D-glucitol (4.38 g, 11.3 mmol) was taken into methyl sulfoxide (30 mL) followed by addition of potassium fluoride (7.5 g, 128 mmol) and the mixture was heated to 180°C over 12 hours. The mixture was cooled to room temperature and partitioned with ethyl acetate and water. The organic layer was washed with water (3x) then brine and dried over anhydrous magnesium sulfate.
  • 1,4:3,6-Dianhydro-2-deoxy-2-fluoro-5- O - ⁇ 2-(methyloxy)-4-[(methyloxy)carbonyl] phenyl ⁇ -L-iditol (4.8 g, 15.4 mmol) was taken into dichloromethane (45 mL) and the solution cooled to 0°C. Fuming nitric acid (90% reagent, 1.3 mL) was added dropwise to the solution followed by addition of concentrated sulfuric acid (0.3 mL). Two additional aliquots of both acids were added at ten minute intervals and the mixture was allowed to warm to room temperature with stirring an additional 20 minutes.
  • the material was hydrogenated at 50 psi hydrogen gas pressure in a Parr apparatus in methanol solution (50 mL) using 10% Pd/C catalyst (1.0 g) over 12 hours. Filtration of the catalyst and concentration of the organic solution afforded 5-O- ⁇ 5-amino-2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl ⁇ -1,4:3,6-dianhydro-2-deoxy-2-fluoro-L-iditol (4.5 g, 90% overall yield) as a solid.
  • 1,4:3,6-Dianhydro-2-deoxy-2-fluoro-5- O -[6-(methyloxy)-4-oxo-3,4-dihydro-quinazolin-7-yl]-L-iditol (3.61 g, 11.2 mmol.) was suspended in chloroform (50 mL) followed by addition of DMF (1.0 mL) and oxalyl chloride (2.0 mL) then the mixture was brought to reflux for 10 minutes then cooled followed by addition of DMF (0.5 mL) and oxalyl chloride (1.0 mL) and the mixture was brought to reflux an additional hour.
  • N- ⁇ [4-(chloromethyl)-1,3-thiazol-2-yl]methyl ⁇ -N,N-dimethylamine hydrochloride hydrochloride (0.019 g, 0.084 mmol) was added and the mixture was stirred at 70°C for a further 25 h.
  • the reaction mixture was concentrated in vacuo. and the residue was partitioned between ethyl acetate and brine. The organic portion was washed with 1 N aqueous sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated in vacuo. to afford a brown solid.
  • Morpholin-4-ylacetonitrile (1.03 g, 8.17 mmol) was added to a mixture of DMF (3.5 mL) and triethylamine (1.4 mL). Hydrogen sulfide gas was bubbled into the solution until the solution was light green. The solution was then heated at 70°C for 0.5 h. Excess hydrogen sulfide was removed from the system by bubbling nitrogen into the solution and then the volatiles were removed in vacuo to afford brown crystals. These crystals were triturated with ethanol to afford 2-morpholin-4-ylethanethioamide as very pale brown crystals (0.525 g, 3.28 mmol, 40% yield).
  • Aqueous formaldehyde (37%, 894 ml, 12.0 mmol) was added to a solution of N-(3,4-dichlorophenyl)-6-(methyloxy)-7- ⁇ [(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]oxy ⁇ quinazolin-4-amine (1g, 2.0mmol) in formic acid (2ml).
  • the mixture was heated at 95°C for two hours. The volatiles were removed under vacuum, the residue was dissolved in CH 3 OH and the pH of the solution was adjusted to 9 by addition of Biorad AG ® 1-X8 hydroxide form resin.
  • 1,1-Dimethylethyl 1-piperazinecarboxylate (25g, 134.2 mmol) was taken into THF (100mL) followed by addition of triethylamine (25mL, 178 mmol). The solution was cooled to 0°C follwed by addition dropwise addition of cyanogen bromide (15.6g, 147.6 mmol) in THF (100mL) and the resulting mixture was allowed to warm to room temperature then stirred an additional 12 hours. The reaction mixture was concentrated in vacuo and partitioned with ethyl ether and water.
  • 1,1-Dimethylethyl 4-cyanopiperazine-1-carboxylate (10g, 47.1 mmol) was taken into ethanol (100mL) and the resulting solution was cooled to 0°C. Hydroxylamine (50% aqueous solution, 3.5mL, 56.5 mmol) was added and the mixture was allowed to warm to room temperature then stirred an additional hour. The mixture was then concentrated in vacuo to a paste and suspended in 1:1 ethyl ether / hexane (100mL) and the solid product collected by filtration.
  • 1,1-Dimethylethyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (3.58g, 14.6 mmol) was suspended in THF (50mL) followed by the addition of diisopropylethylamine (3.0mL, 17.5 mmol) and the mixture was cooled to 0°C.
  • Acetoxyacetyl chloride (1.6mL, 14.6 mmol) was added by syringe and the mixture was allowed to stir an additional 30 minutes at 0°C. The resulting homogeneous solution was allowed to warm to room temperature then concentrated in vacuo to afford a white solid residue.
  • the material was suspended in water (50ml) and the solid product was collected by filtration, washed with additional water then hexanes and dried in vacuo.
  • the intermediate O-acyl derivative was then suspended in THF (50mL) followed by addition of TBAF (1.0M in THF, 3.5mL) and the mixture was stirred for 30 minutes at room temperature.
  • the homogeneous solution obtained was concentrated in vacuo and the residue partitioned with ethyl ether and water.
  • the organic layer was washed twice with additional water then with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate.
  • 1,1-Dimethylethyl 4- ⁇ 5-[(acetoxy)methyl]-1,2,4-oxadiazol-3-yl ⁇ piperazine-1-carboxylate (13.57g, 41.6 mmol) was dissolved in methanol (100mL) followed by addition of aqueous sodium hydroxide (4M, 10.4mL) and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned with ethyl acetate and 0.1M aqueous hydrochloric acid. The organic layer was then washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate.
  • 1,1-Dimethylethyl 4-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (7.4g, 26 mmol) was taken into dichloromethane (100mL) followed by addition of pyridine (5.3mL, 65 mmol) and the solution was cooled to 0°C. Thionyl chloride (2.3mL, 31.2 mmol) was added by syringe and the mixture was allowed to warm to room temperature and stirred an additional 12 hours. The mixture was then concentrated in vacuo and the residue partitioned with ethyl acetate and water.
  • 1,1-dimethylethyl 4-[5-( ⁇ [4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy ⁇ methyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (170mg, 0.28 mmol) was taken into methanol (2.5mL) followed by addition of anhydrous hydrogen chloride in dioxane (4M, 2.5mL) and the mixture was brought to reflux then immediately allowed to cool to room temperature over 5 minutes. The mixture was then concentrated in vacuo to a slurry followed by addition of excess ethyl ether.
  • N-(3,4-dichlorophenyl)-6-(methyloxy)-7- ⁇ [(3-piperazin-1-yl-1,2,4-oxadiazol-5-yl)methyl ⁇ oxyquinazolin-4-amine hydrochloride (66mg, 0.12 mmol) was suspended in methanol (5mL) followed by addition of Bio-Rad AG ® 1-X8 hydroxide form resin until pH 8. The resin was then removed by filtration and the methanol solution was concentrated in vacuo. The residue was taken into formic acid (2mL) and 37W% aqueous formaldehyde (50uL, 0.6 mmol) was added. The mixture was heated to 90°C for 2.5 hours then concentrated in vacuo.
  • N -(3,4-Dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine (0.247 g, 0.506 mmol) was combined with 37% aqueous formaldehyde (0.23 mL, 3.1 mmol) in formic acid (2 mL) and the solution was heated at 95°C for 1 h. The solvent was removed in vacuo and the residue was purified via HPLC (reverse-phase, CH 3 CN/H 2 O with 0.1% TFA).
  • N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine (0.249 g, 0.510 mmol) was taken up in 50% THF/MeOH (10 mL) and the solution was cooled with an ice bath. Acetaldehyde (0.057 mL, 1.0 mmol), followed by NaCNBH 3 (0.038 g, 0.61 mmol) were added. The solution was allowed to warm to room temperature.
  • 1,1-Dimethylethyl 4-(aminocarbonothioyl)piperidine-l-carboxylate (1.50 g, 6.14 mmol), NaHCO 3 (0.570 g, 6.78 mmol) and 1,3-dichloroacetone (0.860 g, 6.77 mmol) were combined in 1,2-dichloroethane (4 mL) and the reaction mixture was stirred at room temperature for 12 h.
  • the crude reaction mixture was filtered using CH 2 Cl 2 and the filtrate was concentrated in vacuo until approximately 30 mL of solvent remained. To this solution was added pyridine (0.75 mL, 9.2 mmol), and the solution was cooled with an ice bath.
  • N -(3,4-Dichlorophenyl)-6-(methyloxy)-7- ⁇ [(2-piperidin-4-yl-1,3-thiazol-4-yl)methyl]oxy ⁇ quinazolin-4-amine (0.078 g, 0.15 mmol) was combined with 37% aqueous formaldehyde (0.025 mL, 0.34 mmol) in formic acid (2 mL) and the solution was heated to 95°C for 1 h. The solvent was removed in vacuo and the residue was taken up in 10% MeOH/ethyl acetate (100 mL) and washed with saturated NaHCO 3 (aq) (100 mL).
  • N -(3,4-Dichlorophenyl)-6-(methyloxy)-7- ⁇ [(2-piperidin-4-yl-1,3-thiazol-4-yl)methyl]oxy ⁇ quinazolin-4-amine (0.230 g, 0.445 mmol) was taken up in 50% MeOH/THF (10 mL) and cooled with an ice bath. Acetaldehyde (0.050 mL, 0.89 mmol) was added, followed by NaCNBH 3 (0.034 g, 0.54 mmol) and the solution was allowed to warm to room temperature. After 1.5 h, 0.016 g (0.25 mmol) of additional NaCNBH 3 was added and the solution was stirred for 12 h.
  • reaction mixture was poured into ethyl acetate (100 mL), washed with saturated NaHCO 3 (aq) (50 mL) and dried (Na 2 SO 4 ). Filtratation and concentration in vacuo was followed by preparative HPLC (reverse-phase, CH 3 CN/H 2 O with 0.01 % TFA). This product was neutralized (NaHCO 3 ) to give 0.167 g (0.306 mmol) of free amine, which was taken up in MeOH (50 mL) and treated with 4.0 M HCl/dioxane (0.077 mL, 0.31 mmol).
  • Lyophilization provided 0.105 g (41%) of N -(3,4-dichlorophenyl)-7-( ⁇ [2-(1-ethylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl ⁇ oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride as a pale yellow solid.
  • ephrin, EGFR, or a compound according to the invention is non-diffusably bound to an insoluble support having isolated sample-receiving areas (for example, a microtiter plate, an array, etc.).
  • the insoluble support may be made of any composition to which the compositions can be bound, is readily separated from soluble material, and is otherwise compatible with the overall method of screening.
  • the surface of such supports may be solid or porous and of any convenient shape. Examples of suitable insoluble supports include microtiter plates, arrays, membranes and beads. These are typically made of glass, plastic (for example, polystyrene), polysaccharides, nylon or nitrocellulose, TeflonTM, etc.
  • Microtiter plates and arrays are especially convenient because a large number of assays can be carried out simultaneously, using small amounts of reagents and samples.
  • the particular manner of binding of the composition is not crucial so long as it is compatible with the reagents and overall methods of the invention, maintains the activity of the composition and is nondiffusable.
  • Exemplary methods of binding include the use of antibodies (which do not sterically block either the ligand binding site or activation sequence when the protein is bound to the support), direct binding to "sticky" or ionic supports, chemical crosslinking, the synthesis of the protein or agent on the surface, etc. Following binding of the protein or agent, excess unbound material is removed by washing. The sample receiving areas may then be blocked through incubation with bovine serum albumin (BSA), casein or other innocuous protein or other moiety.
  • BSA bovine serum albumin
  • K i is defined as the dissociation rate constant for the interaction of the agent with ephrin or EGFR.
  • Exemplary compositions have K i 's of, for example, less than about 100 ⁇ M, less than about 10 ⁇ M, less than about 1 ⁇ M, and further for example having K i 's of less than about 100 nM, and still further, for example, less than about 10 nM.
  • the K i for a compound is determined from the IC 50 based on three assumptions. First, only one compound molecule binds to the enzyme and there is no cooperativity.
  • the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations).
  • the enzymatic rate of the enzyme-inhibitor complex is zero.
  • V is the observed rate
  • V max is the rate of the free enzyme
  • I 0 is the inhibitor concentration
  • E 0 is the enzyme concentration
  • K d is the dissociation constant of the enzyme-inhibitor complex.
  • GI 50 defined as the concentration of the compound that results in a decrease in the rate of cell growth by fifty percent.
  • Exemplary compounds have GI 50 's of, for example, less than about 1 mM, less than about 10 ⁇ M, less than about 1 ⁇ M, and further, for example, having GI 50 's of less than about 100 nM, still further having GI 50 's of less than about 10 nM.
  • Measurement of GI 50 is done using a cell proliferation assay.
  • Tyrosine kinase activity is determined by 1) measurement of kinase-dependent ATP consumption by in the presence of a generic substrate such as polyglutamine, tyrosine (pEY), by luciferase/luciferin-mediated chemiluminescence or; 2) incorporation of radioactive phosphate derived from 33 P-ATP into a generic substrate which has been adsorbed onto the well surface of polystyrene microtiter plates. Phosphorylated substrate products are quantified by scintillation spectrometry.
  • a generic substrate such as polyglutamine, tyrosine (pEY)
  • luciferase/luciferin-mediated chemiluminescence or incorporation of radioactive phosphate derived from 33 P-ATP into a generic substrate which has been adsorbed onto the well surface of polystyrene microtiter plates.
  • Phosphorylated substrate products are quantified by scintillation spectrometry.
  • ATP concentrations are selected near its Michaelis-Menten constant (K M ) for each individual kinase.
  • K M Michaelis-Menten constant
  • Greiner 384-well white clear bottom high binding plates (available from Greiner Bio-One, Inc., of Longwood, Florida) are coated with 2 ⁇ g/well of protein or peptide substrate in a 50 ⁇ L volume overnight at ambient temperature.
  • the coating buffer contains 40 ⁇ g/mL substrate, 22.5 mM Na 2 CO 3 , 27.5 mM NaHCO 3 , 150 mM NaCl and 3 mM NaN 3 .
  • the coating solution is aspirated and the plates are washed once with 50 ⁇ L of assay buffer and padded dry. Subsequently compounds and enzymes are mixed with y 33 P-ATP (3.3 ⁇ Ci/nmol) in a total volume of 20 uL in suitable assay buffers (see Table 2).
  • the final EphB4 reaction solution contains 20 mM TrisHCl, pH 7.5, 10 mM MgCl 2 , 0.01% Triton X-100, 0.1 mM NaVO 3 , 5 nM EphB4 enzyme and 5 ⁇ M ATP.
  • the mixture is incubated at ambient temperature for 1.5-2.5 hrs as indicated in Table 2 and stopped by aspirating using an EMBLA 96-head washer.
  • the plates are subsequently washed 6-12 times with PBST or TBS buffer.
  • kinase activity is measured by the ATP consumption that is accurately measured by luciferase-coupled chemiluminescence.
  • Greiner 384-well white clear bottom medium binding plates are used for LCCA. Briefly the kinase reaction is initiated by mixing compounds, ATP and kinases in a 20 ⁇ L volume. The mixture is incubated at ambient temperature for 2-4 hrs as indicated in Table 2. At the end of the kinase reaction, a 20 ⁇ L luciferase-luciferin mix is added and the chemiluminescent signal is read on a Wallac Victor 2 reader.
  • the luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5 ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mL coenzyme A, 63 ⁇ M AMP, 28 ug/mL luciferin and 40,000 units of light/mL luciferase.
  • the ATP consumption has been kept at 25-45%, where the decrease in substrate concentration has less than 35% effect on IC 50 values compared to the "theoretical" values with no substrate turnover.
  • the IC 50 values correlates well with those of radiometric assays.
  • Enzymes were purchased from Proqinase (of Freiburg, Germany) and Panvera (of Madison, Wisconsin).
  • EphB4 and EphA2 refer to ephrin receptor tyrosine kinse family members ephrin B4 and A2; KDR, kinase insert domain receptor tyrosine kinase, and Flt-1, fms-like tyrosine kinase-1, are representative of the FLK family or receptor tyrosine kinases; EGFR, epidermal growth factor receptor tyrosine kinase, and ErbB2 are representative of the HER family of receptor tyrosine kinases.

Claims (12)

  1. Un composé sélectionné parmi N-(3,4-dichloro-2-fluorophényl)-7-({[(3aR,5r,6aS)-2-méthyloctahydrocyclopenta [c]pyrrol-5-yl]méthyl}oxy)-6-(méthyloxy)quinazolin-4-amine ou N-(3,4-dichloro-2-fluorophényl)-7-({[(3aR,5s,6aS)-2-méthyloctahydrocyclopenta[c]pyrrol-5-yl]méthyl}oxy)-6-(méthyloxy)quinazolin-4-amine, facultativement sous forme d'un sel ou hydrate acceptable d'un point de vue pharmaceutique de celui-ci.
  2. Une composition pharmaceutique comprenant N-(3,4-dichloro-2-fluorophényl)-7-({[(3aR,5r,6aS)-2-méthyloctahydrocyclopenta [c]pyrrol-5-yl]méthyl}oxy)-6-(méthyloxy)quinazolin-4-amine et/ou N-(3,4-dichloro-2-fluorophényl)-7-({[(3aR,5s,6aS)-2-méthyloctahydrocyclopenta[c]pyrrol-5-yl]méthyl}oxy)-6-(méthyloxy)quinazolin-4-amine, facultativement sous forme d'un sel ou hydrate acceptable d'un point de vue pharmaceutique de ceux-ci, de pair avec un véhicule acceptable d'un point de vue pharmaceutique.
  3. Le composé N-(3,4-dichloro-2-fluorophényl)-7-({[(3aR,5r,6aS)-2-méthyloctahydrocyclopenta [c]pyrrol-5-yl]méthyl}oxy)-6-(méthyloxy)quinazolin-4-amine et/ou N-(3,4-dichloro-2-fluorophényl)-7-({[(3aR,5s,6aS)-2-méthyloctahydrocyclopenta[c]pyrrol-5-yl]méthyl}oxy)-6-(méthyloxy)quinazolin-4-amine, facultativement sous forme d'un sel ou hydrate acceptable d'un point de vue pharmaceutique de ceux-ci, facultativement de pair avec un véhicule acceptable d'un point de vue pharmaceutique, destiné à l'utilisation dans le traitement du cancer.
  4. Le composé destiné à l'utilisation de la revendication 3, dans lequel le cancer est sélectionné dans le groupe consistant en cancer du poumon de type non à petites cellules, glioblastome multiforme, cancer du pancréas, cancer du système nerveux, cancer du gros intestin, myélome multiple, carcinome bronchique de type à petites cellules indifférenciées, cancer gastrointestinal, cancer de l'oesophage, mélanome malin, neuroblastome, ostéosarcome, cancer de l'ovaire, cancer de l'endomètre, cancer du col utérin, cancer de la vessie, cancer de l'urètre, et cancer de la prostate.
  5. Le composé destiné à l'utilisation de la revendication 3, dans lequel le cancer est le cancer du poumon.
  6. Le composé destiné à l'utilisation de la revendication 3, dans lequel le cancer est le cancer gastrointestinal.
  7. Le composé destiné à l'utilisation de la revendication 3, dans lequel le cancer est le cancer de la prostate.
  8. La composition pharmaceutique de la revendication 2 ou le composé destiné à l'utilisation de la revendication 3, sous une forme destinée à l'administration par voie orale.
  9. La composition pharmaceutique de la revendication 2 ou le composé destiné à l'utilisation de la revendication 3, sous une forme destinée à l'administration par voie intraveineuse.
  10. Une quantité efficace du composé de la revendication 1, et facultativement sous forme d'un sel ou hydrate acceptable d'un point de vue pharmaceutique de celui-ci destiné à l'utilisation dans l'inhibition du EGFR.
  11. Une quantité efficace du composé de la revendication 1, et facultativement sous forme d'un sel ou hydrate acceptable d'un point de vue pharmaceutique de celui-ci destiné à l'utilisation dans l'inhibition de ErbB2.
  12. Un composé de la revendication 1 destiné à l'utilisation en thérapie.
EP10183590A 2002-07-15 2003-07-14 Composés, compositions pharmaceutiques les contenants et leur utilisation pour traiter le cancer Expired - Lifetime EP2277867B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US39626902P 2002-07-15 2002-07-15
US44721203P 2003-02-13 2003-02-13
EP03764599.1A EP1521747B1 (fr) 2002-07-15 2003-07-14 Modulateurs de kinase de type recepteur et procedes d'utilisation

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP03764599.1A Division-Into EP1521747B1 (fr) 2002-07-15 2003-07-14 Modulateurs de kinase de type recepteur et procedes d'utilisation
EP03764599.1 Division 2003-07-14

Publications (3)

Publication Number Publication Date
EP2277867A2 EP2277867A2 (fr) 2011-01-26
EP2277867A3 EP2277867A3 (fr) 2011-03-23
EP2277867B1 true EP2277867B1 (fr) 2012-12-05

Family

ID=30118575

Family Applications (3)

Application Number Title Priority Date Filing Date
EP03764599.1A Expired - Lifetime EP1521747B1 (fr) 2002-07-15 2003-07-14 Modulateurs de kinase de type recepteur et procedes d'utilisation
EP10183590A Expired - Lifetime EP2277867B1 (fr) 2002-07-15 2003-07-14 Composés, compositions pharmaceutiques les contenants et leur utilisation pour traiter le cancer
EP10184164.1A Expired - Lifetime EP2280003B1 (fr) 2002-07-15 2003-07-14 Procédé pour la préparation de modulateurs de kinases de type récepteur

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP03764599.1A Expired - Lifetime EP1521747B1 (fr) 2002-07-15 2003-07-14 Modulateurs de kinase de type recepteur et procedes d'utilisation

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP10184164.1A Expired - Lifetime EP2280003B1 (fr) 2002-07-15 2003-07-14 Procédé pour la préparation de modulateurs de kinases de type récepteur

Country Status (7)

Country Link
US (5) US7576074B2 (fr)
EP (3) EP1521747B1 (fr)
JP (2) JP4703183B2 (fr)
AU (2) AU2003249212C1 (fr)
CA (1) CA2491191C (fr)
ES (1) ES2400339T3 (fr)
WO (1) WO2004006846A2 (fr)

Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003249212C1 (en) * 2002-07-15 2011-10-27 Symphony Evolution, Inc. Receptor-type kinase modulators and methods of use
MXPA05012839A (es) * 2003-05-27 2006-05-17 Pfizer Prod Inc Quinazolinas y pirido[3,4-d] pirimidinas como inhibidores de receptores tirosina quinasa.
JP2007505871A (ja) * 2003-09-16 2007-03-15 アストラゼネカ アクチボラグ キナゾリン誘導体
BRPI0414532B1 (pt) 2003-09-19 2018-06-05 Astrazeneca Ab Composto derivado de quinazolina, processo para preparar 0 mesmo, composição farmaceutica, e, uso de um composto derivado de quinazolina
GB0322409D0 (en) * 2003-09-25 2003-10-29 Astrazeneca Ab Quinazoline derivatives
EP2213661B1 (fr) 2003-09-26 2011-07-20 Exelixis Inc. Modulateurs c-Met et produits d'utilisation
US20050148605A1 (en) 2003-11-13 2005-07-07 Ambit Biosciences Corporation Amide derivatives as ABL modulators
KR20070097540A (ko) * 2004-12-22 2007-10-04 바이엘 쉐링 파마 악티엔게젤샤프트 퀴놀린 유도체, 그것의 용도 및 제조, 그것을 함유하는제약제
FR2889200B1 (fr) 2005-07-27 2008-01-04 Inst Vaisseaux Et Du Sang Ass Systeme marqueur cellulaire/ligand, ou le marqueur est du type eph, materiau cellulaire comprenant ce systeme, procede de preparation et utilisation proangiogenique
AU2007214427B2 (en) * 2006-02-16 2011-11-10 Ventana Medical Systems, Inc. Reagents and methods for cancer prognosis and pathological staging
WO2008020302A2 (fr) * 2006-08-17 2008-02-21 Pfizer Products Inc. Composés hétéro-aromatiques à base de quinoline
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US7638541B2 (en) 2006-12-28 2009-12-29 Metabolex Inc. 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine
DK2139484T3 (da) 2007-04-10 2013-10-21 Exelixis Inc Fremgangsmåder til behandling af cancer ved brug af pyridopyrimidinon-inhibitorer af PI3K-alfa
DE102007024470A1 (de) 2007-05-24 2008-11-27 Bayer Schering Pharma Aktiengesellschaft Neue Sulfoximin-substituierte Chinolin- bzw. Chinazolinderivate als Kinase-Inhibitoren
US8183381B2 (en) 2007-07-19 2012-05-22 Metabolex Inc. N-linked heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders
EP2072502A1 (fr) 2007-12-20 2009-06-24 Bayer Schering Pharma Aktiengesellschaft Dérivés de chinoline substitués par du sulfoximide et dérivés de chinazoline en tant qu'inhibiteurs de kinase
TWI429404B (zh) * 2008-03-03 2014-03-11 Senomyx Inc 異山梨醇衍生物及彼等作為風味改良劑、促味劑及促味增強劑之用途
PT2268623E (pt) 2008-03-17 2015-09-17 Ambit Biosciences Corp Derivados de quinazolina como moduladores de cinase raf e métodos para utilização dos mesmos
EP2532657B9 (fr) * 2008-10-14 2017-04-19 Sunshine Lake Pharma Co., Ltd. Composés et procédés d'utilisation
TWI641593B (zh) 2009-01-16 2018-11-21 美商艾克塞里克斯公司 包含ｎ-（４-｛〔６，７-雙（甲氧基）喹啉-４-基〕氧基｝苯基）-ｎ’-（４-氟苯基）環丙烷-１，１-二甲醯胺之蘋果酸鹽之醫藥組合物及其用途
WO2010111063A1 (fr) * 2009-03-21 2010-09-30 Ning Xi Dérivés d'ester d'amino, sels de ceux-ci et procédés d'utilisation
WO2010120889A1 (fr) * 2009-04-14 2010-10-21 Ampla Pharmaceuticals Inc. Traitement du syndrome métabolique par des amides cycliques
FR2945534B1 (fr) * 2009-05-12 2012-11-16 Sanofi Aventis DERIVES DE CYCLOPENTAL[c]PYRROLE-2-CARBOXYLATES, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
EP2272846A1 (fr) * 2009-06-23 2011-01-12 Bayer CropScience AG Dérivés de thiazolylpipéridine en tant que fongicide
UA108618C2 (uk) 2009-08-07 2015-05-25 Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку
US9200007B2 (en) 2009-08-20 2015-12-01 Karus Therapeutics Limited Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors
CN102666553B (zh) 2009-10-01 2015-05-06 赛马拜制药公司 取代的四唑-1-基-苯氧基甲基-噻唑-2-基-哌啶基-嘧啶盐
MX2012006955A (es) * 2009-12-15 2012-12-05 Neurop Inc Compuestos para el tratamiento de trastornos neurologicos.
WO2011149841A1 (fr) 2010-05-25 2011-12-01 Janssen Pharmaceutica Nv Thiazolidinedione indazoles, indoles et benzotriazoles substitués utiles en tant que modulateurs des récepteurs α liés aux œstrogènes
CN103313713B (zh) * 2010-08-26 2014-12-31 和谐进化股份有限公司 受体型激酶调节剂和多囊性肾病的治疗方法
CN102382065B (zh) * 2010-08-30 2014-05-28 山东轩竹医药科技有限公司 苯胺取代的喹唑啉衍生物
CN102382106A (zh) 2010-08-30 2012-03-21 黄振华 苯胺取代的喹唑啉衍生物
EP2640366A2 (fr) 2010-11-15 2013-09-25 Exelixis, Inc. Benzoxazépines en tant qu'inhibiteurs de pi3k/mtor et leurs méthodes d'utilisation et de fabrication
JP6006242B2 (ja) 2011-03-04 2016-10-12 ニューゲン セラピューティクス， インコーポレイテッド アルキン置換キナゾリン化合物および使用方法
WO2012155339A1 (fr) * 2011-05-17 2012-11-22 江苏康缘药业股份有限公司 Dérivés de la 4-phénylamino-6-buténamide-7-alkyloxy quinazoline, leur procédé de préparation et leur utilisation
TWI577671B (zh) 2011-11-14 2017-04-11 Sunshine Lake Pharma Co Ltd Aminoquinazoline derivatives and salts thereof and methods of use thereof
WO2013101964A1 (fr) * 2011-12-27 2013-07-04 Kadmon Corporation, Llc Procédés de traitement d'un cancer du sein ne répondant pas au trastuzumab
CN102643268B (zh) * 2011-12-30 2014-05-21 沈阳药科大学 喹啉类及噌啉类化合物及其应用
GB201204125D0 (en) 2012-03-08 2012-04-25 Karus Therapeutics Ltd Compounds
CN103804308A (zh) * 2012-11-06 2014-05-21 天津药物研究院 7-取代环己基喹唑啉衍生物及其制备方法和用途
US20140303097A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
HUE041709T2 (hu) 2013-04-05 2019-05-28 Boehringer Ingelheim Int Az empagliflozin terápiás alkalmazásai
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
MX2015014512A (es) 2013-04-18 2016-02-09 Boehringer Ingelheim Int Composicion farmaceutica, metodos para tratamiento y sus usos.
EP3052494B1 (fr) 2013-06-28 2018-12-26 H. Hoffnabb-La Roche Ag Composés d'azaindazole en tant qu'inhibiteurs de la t790m contenant des mutants de l'egfr
GB201402431D0 (en) 2014-02-12 2014-03-26 Karus Therapeutics Ltd Compounds
EP3116507B1 (fr) * 2014-03-10 2021-05-26 Kadmon Corporation, LLC Composés pour le traitement de tumeurs du cerveau par voie orale
CN105330653A (zh) * 2014-08-11 2016-02-17 石药集团中奇制药技术（石家庄）有限公司 喹唑啉衍生物
EP3253739A4 (fr) * 2015-02-03 2018-07-18 Trillium Therapeutics Inc. Nouveaux dérivés fluorés utilisés en tant qu'inhibiteurs d'egfr utiles pour le traitement de cancers
AR104882A1 (es) 2015-06-05 2017-08-23 Orion Corp DERIVADOS DE 2-(1-HETEROARILPIPERAZIN-4-IL)METIL-1,4-BENZODIOXANO COMO ANTAGONISTAS DE a2C
GB201514760D0 (en) 2015-08-19 2015-09-30 Karus Therapeutics Ltd Compounds and method of use
GB201514758D0 (en) 2015-08-19 2015-09-30 Karus Therapeutics Ltd Formulation
GB201514751D0 (en) 2015-08-19 2015-09-30 Karus Therapeutics Ltd Compounds
GB201514754D0 (en) 2015-08-19 2015-09-30 Karus Therapeutics Ltd Compounds
US20170066778A1 (en) * 2015-09-04 2017-03-09 Aunova Medchem LLC Solubility for target compounds
CN105294495A (zh) * 2015-09-21 2016-02-03 苏州大学 一种氰甲基酯的制备方法
KR20180086187A (ko) 2015-10-05 2018-07-30 더 트러스티이스 오브 콜롬비아 유니버시티 인 더 시티 오브 뉴욕 자가포식 유동의 활성체 및 포스포리파제 d 및 타우를 포함하는 단백질 응집물의 클리어런스 및 단백질질환의 치료
JP2019527693A (ja) 2016-08-03 2019-10-03 サイマベイ・セラピューティクス・インコーポレイテッドＣｙｍａＢａｙ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． 炎症性胃腸疾患または胃腸状態を治療するためのオキシメチレンアリール化合物
US10799503B2 (en) 2016-12-01 2020-10-13 Ignyta, Inc. Methods for the treatment of cancer
WO2019079783A1 (fr) * 2017-10-20 2019-04-25 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
AU2018360581A1 (en) 2017-10-31 2020-06-11 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
KR20200116945A (ko) 2018-02-02 2020-10-13 반더빌트유니버시티 무스카린성 아세틸콜린 수용체 m4의 길항제
WO2019170086A1 (fr) * 2018-03-06 2019-09-12 北京赛特明强医药科技有限公司 Composé d'oxazino-quinazoline à substitution acyle, son procédé de préparation et ses applications
CN112442045B (zh) * 2019-09-03 2022-02-18 北京赛特明强医药科技有限公司 一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用

Family Cites Families (118)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2705832B1 (fr) * 1993-05-28 1995-06-30 Commissariat Energie Atomique Procédé de réalisation d'un cordon d'étanchéité et de tenue mécanique entre un substrat et une puce hybridée par billes sur le substrat.
GB9510757D0 (en) 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
TW321649B (fr) 1994-11-12 1997-12-01 Zeneca Ltd
GB9508538D0 (en) * 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
US5747498A (en) * 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US5650415A (en) * 1995-06-07 1997-07-22 Sugen, Inc. Quinoline compounds
CA2222545A1 (fr) * 1995-06-07 1996-12-19 Sugen, Inc. Quinazolines et compositions pharmaceutiques
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
GB9523675D0 (en) * 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
GB9624482D0 (en) 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
NZ325248A (en) * 1995-12-23 1999-09-29 Pfizer Res & Dev Quinoline and quinazoline compounds useful in therapy
TR199801530T2 (xx) 1996-02-13 1998-11-23 Zeneca Limited VEGF �nhibit�rleri olarak kinazolin t�revleri.
GB9603095D0 (en) * 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
PT885198E (pt) 1996-03-05 2002-06-28 Astrazeneca Ab Derivados de 4-anilinoquinazolina
JP2000506880A (ja) * 1996-03-15 2000-06-06 ゼネカ・リミテッド シンノリン誘導体及びその使用
PL190489B1 (pl) * 1996-04-12 2005-12-30 Warner Lambert Co Nieodwracalne inhibitory kinaz tyrozyny, kompozycja farmaceutyczna je zawierająca i ich zastosowanie
EP0912559B1 (fr) * 1996-07-13 2002-11-06 Glaxo Group Limited Composes heterocycliques condenses en tant qu'inhibiteurs de la proteine tyrosine kinase
HRP970371A2 (en) 1996-07-13 1998-08-31 Kathryn Jane Smith Heterocyclic compounds
DE69733825T2 (de) 1996-09-25 2006-06-08 Astrazeneca Ab Chinolin-derivate die den effekt von wachstumsfaktoren wie vegf vezögern
GB9718972D0 (en) * 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
GB9700504D0 (en) * 1997-01-11 1997-02-26 Pfizer Ltd Pharmaceutical compounds
GB9705361D0 (en) * 1997-03-14 1997-04-30 Celltech Therapeutics Ltd Chemical compounds
UA73073C2 (uk) 1997-04-03 2005-06-15 Уайт Холдінгз Корпорейшн Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція
ES2207834T3 (es) 1997-04-22 2004-06-01 Janssen Pharmaceutica N.V. Quino- y quinazolinas antagonistas del crf.
GB9708917D0 (en) 1997-05-01 1997-06-25 Pfizer Ltd Compounds useful in therapy
ZA986732B (en) * 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitiors of tyrosine kinases
DE69838172T2 (de) 1997-08-22 2008-04-10 Astrazeneca Ab Oxindolylchinazolinderivate als angiogenesehemmer
RS49779B (sr) * 1998-01-12 2008-06-05 Glaxo Group Limited, Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze
EP1082311A1 (fr) * 1998-05-28 2001-03-14 Parker Hughes Institute Utilisation des quinazolines pour le traitement de tumeurs cerebrales
AU5620299A (en) * 1998-08-11 2000-03-06 Novartis Ag Isoquinoline derivatives with angiogenesis inhibiting activity
HUP0103386A3 (en) * 1998-08-21 2002-07-29 Parker Hughes Inst St Paul Use of quinazoline derivatives for producing pharmaceutical compositions having jak 3-inhibitor effect
US6184226B1 (en) * 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
US6288082B1 (en) * 1998-09-29 2001-09-11 American Cyanamid Company Substituted 3-cyanoquinolines
IL142121A0 (en) 1998-09-29 2002-03-10 American Cyanamid Co Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors
KR20010089284A (ko) * 1998-10-01 2001-09-29 다비드 에 질레스 화합물
ATE294796T1 (de) 1998-10-08 2005-05-15 Astrazeneca Ab Chinazolin derivate
EA003786B1 (ru) * 1998-11-19 2003-10-30 Варнер Ламберт Компани N-[4-(3-хлор-4-фторфениламино)-7-(3-морфолин-4-илпропокси)хиназолин-6-ил]акриламид - необратимый ингибитор тирозинкиназ
KR100787254B1 (ko) 1999-01-22 2007-12-20 기린 홀딩스 가부시키가이샤 퀴놀린유도체 및 퀴나졸린유도체
HU230000B1 (en) 1999-02-10 2015-04-28 Astrazeneca Ab Intermediates for the preparation of angiogenesis inhibitory quinazoline derivatives
GB9904103D0 (en) * 1999-02-24 1999-04-14 Zeneca Ltd Quinoline derivatives
US6080747A (en) * 1999-03-05 2000-06-27 Hughes Institute JAK-3 inhibitors for treating allergic disorders
DE19911509A1 (de) 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
AU3630100A (en) 1999-03-19 2000-10-09 Parker Hughes Institute Quinazoline formulations and therapeutic use thereof
US6258820B1 (en) * 1999-03-19 2001-07-10 Parker Hughes Institute Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
RS49836B (sr) 1999-03-31 2008-08-07 Pfizer Products Inc., Postupci i intermedijeri za dobijanje anti-kancernih jedinjenja
GB9910577D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
US6126917A (en) * 1999-06-01 2000-10-03 Hadasit Medical Research Services And Development Ltd. Epidermal growth factor receptor binding compounds for positron emission tomography
AU775285B2 (en) * 1999-06-21 2004-07-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof
GB9922173D0 (en) 1999-09-21 1999-11-17 Zeneca Ltd Chemical compounds
WO2001021596A1 (fr) 1999-09-21 2001-03-29 Astrazeneca Ab Derives de quinazoline et leur utilisation comme produits pharmaceutiques
PL354923A1 (en) 1999-09-21 2004-03-22 Astrazeneca Ab Quinazoline compounds and pharmaceutical compositions containing them
UA72946C2 (uk) * 1999-11-05 2005-05-16 Астразенека Аб Похідні хіназоліну як інгібітори васкулярного ендотеліального фактора росту (vegf)
US6759410B1 (en) * 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
JP2003518023A (ja) * 1999-11-30 2003-06-03 パーカー ヒューズ インスティテュート トロンビン誘導血小板凝集の阻害剤
US7135466B2 (en) 1999-12-24 2006-11-14 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives and drugs containing the same
US6525046B1 (en) * 2000-01-18 2003-02-25 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
BR0109165A (pt) 2000-03-13 2003-04-22 American Cyanamid Co Método de tratamento de pólipos colÈnicos
US6521618B2 (en) * 2000-03-28 2003-02-18 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
US6608048B2 (en) * 2000-03-28 2003-08-19 Wyeth Holdings Tricyclic protein kinase inhibitors
GB0008269D0 (en) * 2000-04-05 2000-05-24 Astrazeneca Ab Combination chemotherapy
JP4970689B2 (ja) * 2000-04-07 2012-07-11 アストラゼネカ アクチボラグ キナゾリン化合物
US6627634B2 (en) * 2000-04-08 2003-09-30 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US6602836B2 (en) * 2000-05-11 2003-08-05 Unilever Home & Personal Care Usa, A Division Of Conopco, Inc. Machine dishwashing compositions containing cationic bleaching agents and water-soluble polymers incorporating cationic groups
UA73993C2 (uk) 2000-06-06 2005-10-17 Астразенека Аб Хіназолінові похідні для лікування пухлин та фармацевтична композиція
AU2001264159A1 (en) * 2000-06-22 2002-01-02 Pfizer Products Inc. Substituted bicyclic derivatives for the treatment of abnormal cell growth
EP1174118A1 (fr) 2000-06-28 2002-01-23 Cognis France S.A. Utilisation de l'inuline et de dérivés de celui-ci
AU2001266505A1 (en) 2000-06-28 2002-01-08 Astrazeneca Ab Substituted quinazoline derivatives and their use as inhibitors
CA2419301C (fr) 2000-08-21 2009-12-08 Astrazeneca Ab Derives de quinazoline
DE10042058A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6740651B2 (en) * 2000-08-26 2004-05-25 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US6617329B2 (en) 2000-08-26 2003-09-09 Boehringer Ingelheim Pharma Kg Aminoquinazolines and their use as medicaments
US6403580B1 (en) * 2000-08-26 2002-06-11 Boehringer Ingelheim Pharma Kg Quinazolines, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US6656946B2 (en) * 2000-08-26 2003-12-02 Boehringer Ingelheim Pharma Kg Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
DE10042059A1 (de) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6653305B2 (en) * 2000-08-26 2003-11-25 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US6939866B2 (en) 2000-10-13 2005-09-06 Astrazeneca Ab Quinazoline derivatives
EP1326859A1 (fr) 2000-10-13 2003-07-16 AstraZeneca AB Derives quinazoline a activite anti-tumorale
AU2002212436A1 (en) 2000-10-25 2002-05-06 Astrazeneca Ab Quinazoline derivatives
DE60132484T2 (de) 2000-11-02 2009-01-15 Nippon Shinyaku Co., Ltd. Chinazolinderivate und -arzneimittel
AU2001295791A1 (en) 2000-11-02 2002-05-15 Astrazeneca Ab 4-substituted quinolines as antitumor agents
AU2002210714A1 (en) 2000-11-02 2002-06-11 Astrazeneca Ab Substituted quinolines as antitumor agents
US7019012B2 (en) * 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US6900220B2 (en) * 2001-01-02 2005-05-31 Syntex (U.S.A.) Llc Quinazolone derivatives as alpha 1A/B adrenergic receptor antagonists
ES2312557T3 (es) 2001-04-19 2009-03-01 Astrazeneca Ab Derivados de quinazolina.
DK1382604T3 (da) 2001-04-27 2006-04-18 Kirin Brewery Quinolinderivater med en azolylgruppe og quinazolinderivater
SE0101675D0 (sv) 2001-05-11 2001-05-11 Astrazeneca Ab Novel composition
WO2002092577A1 (fr) 2001-05-14 2002-11-21 Astrazeneca Ab Derives quinazoliniques
WO2002092579A1 (fr) 2001-05-14 2002-11-21 Astrazeneca Ab Derives de 4-anilinoquinazoline
WO2002092578A1 (fr) 2001-05-14 2002-11-21 Astrazeneca Ab Derives de quinazoline
WO2003000188A2 (fr) 2001-06-21 2003-01-03 Ariad Pharmaceuticals, Inc. Nouvelles quinazolines et leur utilisation
EP1411046B1 (fr) 2001-06-22 2009-09-16 Kirin Pharma Kabushiki Kaisha Derive de quinoleine et derive de quinoleine permettant d'inhiber l'auto-phosphorylation du recepteur des proliferateurs des hepatocytes, ainsi que des compositions medicinales contenant ce derive
KR100397792B1 (ko) * 2001-06-28 2003-09-13 한국과학기술연구원 4-(페닐아미노)-[1,4]디옥사노[2,3-ｇ]퀴나졸린 유도체 및그의 제조방법
GB0118752D0 (en) * 2001-08-01 2001-09-26 Pfizer Ltd Process for the production of quinazolines
US7169788B2 (en) 2001-10-30 2007-01-30 Merck & Co., Inc. Tyrosine kinase inhibitors
GB0126433D0 (en) 2001-11-03 2002-01-02 Astrazeneca Ab Compounds
GB0128108D0 (en) 2001-11-23 2002-01-16 Astrazeneca Ab Therapeutic use
TW200300348A (en) * 2001-11-27 2003-06-01 American Cyanamid Co 3-cyanoquinolines as inhibitors of egf-r and her2 kinases
AU2002347336A1 (en) 2001-12-05 2003-06-17 Astrazeneca Ab Quinoline derivatives
GB0129099D0 (en) 2001-12-05 2002-01-23 Astrazeneca Ab Chemical compounds
AU2002347359A1 (en) 2001-12-05 2003-06-17 Astrazeneca Ab Quinoline derivatives
WO2003050108A1 (fr) 2001-12-12 2003-06-19 Pfizer Products Inc. Formes salines de e-2-methoxy-n-(3-{4-[3-methl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide
MXPA04004107A (es) * 2001-12-12 2004-07-23 Pfizer Prod Inc Moleculas pequenas para el tratamiento del crecimiento celular anormal.
WO2003055866A1 (fr) 2001-12-21 2003-07-10 Bayer Pharmaceuticals Corporation Composes derives de quinazoline et de quinoline servant d'inhibiteurs de prolylpeptidase, d'inducteurs d'apoptose et d'agents therapeutiques anticancereux
TW200301123A (en) 2001-12-21 2003-07-01 Astrazeneca Uk Ltd New use
MXPA04006260A (es) 2001-12-24 2005-03-31 Astrazeneca Ab Derivados de quinazolina sustituidos como inhibidores de cinasas aurora.
EP1470125A1 (fr) 2002-01-29 2004-10-27 Glaxo Group Limited Derives aminopiperidine
WO2003064431A2 (fr) 2002-01-29 2003-08-07 Glaxo Group Limited Composes aminopiperidine, leur procede de preparation et compositions pharmaceutiques les contenant
AU2003202094B2 (en) 2002-02-01 2009-10-08 Astrazeneca Ab Quinazoline compounds
DE10204462A1 (de) 2002-02-05 2003-08-07 Boehringer Ingelheim Pharma Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse
TW200813014A (en) 2002-03-28 2008-03-16 Astrazeneca Ab Quinazoline derivatives
MXPA04009536A (es) * 2002-03-30 2005-01-25 Boehringer Ingelheim Pharma Compuestos heterociclos biciclicos, composiciones farmaceuticas que contienen estos compuestos, su utilizacion y procesos para su preparacion.
DE10217689A1 (de) 2002-04-19 2003-11-13 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung
AU2003249212C1 (en) * 2002-07-15 2011-10-27 Symphony Evolution, Inc. Receptor-type kinase modulators and methods of use
WO2004035572A1 (fr) 2002-10-21 2004-04-29 Kirin Beer Kabushiki Kaisha Sel de n-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n'-(5-methyl-3-isoxazolyl)uree sous forme cristalline
JP4593464B2 (ja) 2002-11-04 2010-12-08 アストラゼネカ アクチボラグ Ｓｒｃチロシンキナーゼ阻害剤としてのキナゾリン誘導体
TW200418480A (en) 2002-12-13 2004-10-01 Neurogen Corp 2-substituted quinazolin-4-ylamine analogues
PL377686A1 (pl) 2002-12-18 2006-02-06 Pfizer Products Inc. Pochodne 4-anilinochinazoliny do leczenia anormalnego wzrostu komórek
AU2003299943A1 (en) 2002-12-23 2004-07-22 Ariad Pharmaceuticals, Inc. Heterocycles and uses thereof

Also Published As

Publication number Publication date
EP1521747A4 (fr) 2006-10-11
AU2003249212C1 (en) 2011-10-27
US20140155418A1 (en) 2014-06-05
US9359332B2 (en) 2016-06-07
CA2491191C (fr) 2014-02-04
EP2280003B1 (fr) 2014-04-02
US9796704B2 (en) 2017-10-24
AU2010226916B2 (en) 2013-05-16
US20060069077A1 (en) 2006-03-30
EP2280003A2 (fr) 2011-02-02
EP2280003A3 (fr) 2011-03-30
EP2277867A2 (fr) 2011-01-26
AU2003249212B2 (en) 2010-07-01
EP1521747B1 (fr) 2018-09-05
US20160129032A1 (en) 2016-05-12
US20180118724A1 (en) 2018-05-03
WO2004006846A2 (fr) 2004-01-22
US10266518B2 (en) 2019-04-23
US8658654B2 (en) 2014-02-25
JP2011079844A (ja) 2011-04-21
ES2400339T3 (es) 2013-04-09
WO2004006846A3 (fr) 2004-07-15
AU2010226916A1 (en) 2010-10-28
EP2277867A3 (fr) 2011-03-23
JP2006505509A (ja) 2006-02-16
JP4703183B2 (ja) 2011-06-15
CA2491191A1 (fr) 2004-01-22
AU2003249212A1 (en) 2004-02-02
US7576074B2 (en) 2009-08-18
US20090318373A1 (en) 2009-12-24
EP1521747A2 (fr) 2005-04-13

Similar Documents

Publication Publication Date Title
US10266518B2 (en) Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof
US7977345B2 (en) c-MET modulators and method of use
EP1848719B1 (fr) COMPOSES de [1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-YL]-PIPERIDINE ou -piperazine UTILISES EN TANT QUE MODULATEURS DES SERINE-THREONINE KINASES (P70S6K, ATK1 ET ATK2) POUR LE TRAITEMENT DE MALADIES IMMUNOLOGIQUES, INFLAMMATOIRES ET PROLIFERATivES
US7872014B2 (en) Anaplastic lymphoma kinase modulators and methods of use
AU2004230928B2 (en) Tie-2 modulators and methods of use
US7626031B2 (en) Substituted 3-(diarylmethylene)indolin-2-ones and methods of their use

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AC Divisional application: reference to earlier application

Ref document number: 1521747

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

RIN1 Information on inventor provided before grant (corrected)

Inventor name: RICE, KENNETH D.

Inventor name: PETO, CSABE J.

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1147484

Country of ref document: HK

17P Request for examination filed

Effective date: 20110923

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AC Divisional application: reference to earlier application

Ref document number: 1521747

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 587221

Country of ref document: AT

Kind code of ref document: T

Effective date: 20121215

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 60342806

Country of ref document: DE

Effective date: 20130131

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2400339

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20130409

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 587221

Country of ref document: AT

Kind code of ref document: T

Effective date: 20121205

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130306

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130305

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130405

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

26N No opposition filed

Effective date: 20130906

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60342806

Country of ref document: DE

Effective date: 20130906

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20030714

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130714

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 13

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1147484

Country of ref document: HK

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20180720

Year of fee payment: 18

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190714

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20201130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190715

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20220615

Year of fee payment: 20

Ref country code: IE

Payment date: 20220609

Year of fee payment: 20

Ref country code: GB

Payment date: 20220606

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20220609

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20220531

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20220802

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60342806

Country of ref document: DE

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: MK

Effective date: 20230713

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20230713

REG Reference to a national code

Ref country code: IE

Ref legal event code: MK9A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20230714

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20230713